Ischemic disorders such as myocardial infarction and cerebral infarct are one of the major causes of death. Therefore, as the population ages, the social need for the development of the therapeutic medical is increasing. Recently, angiogenic treatment using gene therapy and bone-marrow mononuclear cell transplantation and the like has been investigated as a novel therapy for the ischemic disorders. Major problem of the current angiogenic treatment includes that it is difficult to keep the vascularized blood vessels intact because of their high vascular permeability due their weakness, which may lead to edema, hemorrhage, and restenosis of the blood vessels once vascularized after the treatment. In addition, the use of the growth factors such as vascular endothelial growth factor (VEGF) to the angiogenic treatment includes the risk of developing the arteriosclerotic disease as well. To develop the angiogenic treatment as a safe and effective standard therapy to the ischemic disorders, it is required to solve aforementioned problems and to improve long-term prognosis after treatment.
Major problems of the treatment of cerebral ischemic disorders in the acute phase are management of cerebral edema as well as relief of ischemia. Main aims of the treatment of the cerebral infarction are to recover the function of nerve cells and to protect the uninjured tissue. In the acute phase of cerebral infarction, cerebral edema occurs at site of infarction and its surrounding. In the severe cerebral edema, expansion of the injured area due to the compression of uninjured tissue against cranium as well as the compression of brain-stem which make vital prognosis worse may occur. For cerebral edema, there is no effective therapy other than the administration of the hyperosmotic substances so far. In spite of its importance, there has been no significant progress in the development of the therapy for cerebral edema occurring in conjunction with cerebral infarction and improved drugs for these decades.
A management of the cerebral edema includes the administration of hyperosmotic substances such as glycerol and mannitol. As reported, meta-analysis showed that the administration of the hyperosmotic agents significantly reduced the mortality rate within 14 days after the onset of cerebral infarction. However, there are doubts about long-term prognosis and functional prognosis. To improve the vital prognosis and the functional prognosis after the treatment, a novel therapy based on the mechanism of the onset of the cerebral edema is expected.
Adrenomedullin (AM) is a peptide consisting of 52 amino acids found by Kitamura and Kangawa et al. in 1993. AM attracted attention as a venotropic agent with vasodilating effect when it has been found, however, subsequent studies revealed that it has a variety of physiological activities such as regulation of the cell migration, regulation of differentiation, anti-inflammatory effect, body fluid volume regulating effect, and cardiac effect.
The present inventors have established the transgenic mice in which AM gene overexpress vascular specifically, AM-knockout mice as well as calcitonin gene related peptide (CGRP) (a family of AM) knockout mice and reported the result of the series of studies (Circulation. 2000; 101: 2309; Circulation. 2001; 104: 1964; Circ Res. 2001, 89, 983; Circ Res. 2002; 90:657; Arterioscler Thromb Vasc Biol. 2002 22: 1310-5; Circulation. 2004; 109:1789; Circ Res. 2004; 95: 415). In addition, it has also been reported that organ injury when ischemia and reperfusion injury occurred in kidney was increased in the heterozygotes of AM-knockout mice, which was suppressed, in contrast, in the transgenic mice, which shows that AM is the physiological active substance with not only vasodilating effect but also organ protective effect. Also, it has also been reported that immature blood vessels and significant abnormality in the blood vessel wall itself were observed in the homozygotes of AM-knockout mice, which were lethal at the 14th embryonic day of embryonic life due to the hemorrhage and the systemic edema (Circulation, 2001; 104; 1964).